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Preservation of peptide specificity during TCR-MHC contact dominated affinity enhancement of a melanoma-specific TCR
Structural highlights
DiseaseTRAC_HUMAN TCR-alpha-beta-positive T-cell deficiency. The disease is caused by variants affecting the gene represented in this entry. FunctionTRAC_HUMAN Constant region of T cell receptor (TR) alpha chain (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).[1] [2] [3] [4] Publication Abstract from PubMedThe T-cell receptor (TCR) recognises peptides bound to major histocompatibility molecules (pMHC) and allows T-cells to interrogate the cellular proteaome for internal anomalies from the cell surface. The TCR contacts both MHC and peptide in an interaction characterised by weak affinity (KD >1 muM). We used phage-display to produce a melanoma-specific TCR (alpha24beta17) with a >30,000-fold enhanced binding affinity (KD = 600 pM) in order to aid our exploration of the molecular mechanisms utilised to maintain peptide specificity. Remarkably, although the enhanced affinity was mediated primarily through new TCR-MHC contacts, alpha24beta17 remained acutely sensitive to modifications at every position along the peptide backbone, mimicking the specificity of the wild type TCR. Thermodynamic analyses revealed an important role for solvation in directing peptide specificity. These findings advance our understanding of the molecular mechanisms that can govern the exquisite peptide specificity characteristic of TCR recognition. T-cell receptor specificity maintained by altered thermodynamics.,Madura F, Rizkallah PJ, Miles KM, Holland CJ, Bulek AM, Fuller A, Schauenburg AJ, Miles JJ, Liddy N, Sami M, Li Y, Hossain M, Baker BM, Jakobsen BK, Sewell AK, Cole DK J Biol Chem. 2013 May 22. PMID:23698002[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
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